Imidazole derivatives having affinity for α2 receptors

ABSTRACT

Imidazole derivatives of formula I                    
     wherein n is 0 or 1, R 1  is hydrogen or C 1 -C 4 -alkyl, R 2  is hydrogen or R 2  and R 3  together form a double bond, R 3  is hydrogen or C 1 -C 4 -alkyl or R 2  and R 3  together form a double bond, R 4  is hydrogen, C 1 -C 4 -alkyl, hydroxy or C 1 -C 4 -alkoxy, R 5  is hydrogen or C 1 -C 4 -alkyl or R 4  and R 5  together with the carbon atom to which they are attached form a carbonyl group, R 6 , R 7  and R 8  are each the same or different and are independently hydrogen, C 1 -C 4 -alkyl or C 2 -C 4 -alkenyl, C 3 -C 7 -cycloalkyl, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -hydroxyalkyl, thiol, C 1-4 -alkylthio, C 1-4 -alkylthiol, halogen, trifluoromethyl, nitro or optionally substituted amino, X is —CHR 9 —(CHR 10 ) m —, m is 0 or 1, and R 9  and R 10  are each the same or different and are independently hydrogen or C 1 -C 4 -alkyl; or a pharmaceutically acceptable ester or salt thereof, their preparation, use and pharmaceutical compositions comprising them are described. The compounds have affinity for alpha2 receptors and are useful e.g. in the treatment of hypertension, glaucoma, chronic or acute pain, migraine, diarrhea, common cold, ischemia, addiction to chemical substances, anxiety, especially preoperative anxiety and different neurological, musculoskeletal, psychiatric and cognition disorders or as adjuncts to anesthesia.

This application is a continuation of application Ser. No. 09/051,151,filed Feb. 2, 1999, now U.S. Pat. No. 6,313,311, which is incorporatedherein by reference, and which is a national stage filing ofPCT/FI96/00518, filed on Oct. 2, 1996, which published in the Englishlanguage.

The present invention relates to substituted 4(5)-(1-indanyl and1-indanylmethyl and 1-indanylmethylen)imidazoles and4(5)-[1-(1,2,3,4-tetrahydronaphthyl and 1,2,3,4-tetrahydronaphthylmethyland 1,2,3,4-tetrahydronaphthylmethylen]imidazoles and to their isomers,pharmaceutically acceptable salts and esters. It also relates to theirpreparation, use and to pharmaceutical compositions containing them.

The compounds of the invention have affinity for alpha2 receptors mostof them being very selective alpha2 agonists. Accordingly, they areuseful in the treatment of hypertension, glaucoma, migraine, diarrhea,ischemia, addiction to chemical substances (such as tobacco andnarcotics) and different neurological, musculoskeletal, psychiatric andcognition disorders as well as sedative and analgesic agents, nasaldecongestants, and adjuncts to anaesthesia.

Gregory G. B., et al describe in J. Org. Chem. (1990), 55, 1479-1483 anew synthesis step for1-phenylalkyl-1-(4-imidazolyl)-1,2,3,4-tetrahydronaphthalene derivativeswhich are useful as nonpeptide antagonists of the angiotensin IIreceptor.

The imidazole derivatives of the invention are either compounds offormula I

n is 0 or 1

R₁ is hydrogen or C₁-C₄-alkyl

R₂ is hydrogen or R₂ and R₃ together form a double bond

R₃ is hydrogen or C₁-C₄-alkyl or R₂ and R₃ together form a double bond

R₄ is hydrogen, C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy

R₅ is hydrogen or C₁-C₄-alkyl or R₄ and R₅ together with the carbon atomto which they are attached form a carbonyl group

R₆, R₇ and R₈ are each the same or different and are independentlyhydrogen, C₁-C₄-alkyl or C₂-C₄-alkenyl, C₃-C₇-cycloalkyl, hydroxy,C₁-C₄-alkoxy, C₁-C₄-hydroxyalkyl, thiol, C₁₋₄-alkylthio,C₁₋₄-alkylthiol, halogen, trifluoromethyl, nitro or optionallysubstituted amino

X is —CHR₉—(CHR₁₀)_(m)—

m is 0 or 1

and R₉ and R₁₀ are each the same or different and are independentlyhydrogen or C₁-C₄-alkyl;

or a pharmaceutically acceptable ester or salt thereof.

The terms as employed herein have the following meanings: A halogen ise.g. chlorine, bromine or fluorine, preferably it is chlorine orfluorine. The C₁-C₄-alkyl, C₁-C₄-alkoxy and C₂-C₄-alkenyl etc. groupsmay be branched or straight chain groups. C₃-C₇-Cycloalkyl is asaturated cyclic hydrocarbon group having preferably 3 to 5 carbonatoms. Optionally substituted amino is an amino group which isunsubstituted or substituted with a C₁-C₄-alkyl group.

When m=n=0

R₃ is preferably hydrogen,

R₄ is preferably hydrogen, hydroxy or C₁-C₄-alkoxy, such as ethoxy,

R₅ is preferably hydrogen, or R₄ and R₅ form, together with the carbonatom to which they are attached, a carbonyl group.

R₆ is preferably hydrogen, C₁-C₄-alkyl or C₁-C₄-alkoxy, such as methyl,ethyl, t-butyl, methoxy or hydroxy. For example, R₆ may be C₁-C₄-alkylat position 4, 5 or 6, a C₁-C₄-alkoxy at position 5, 6 or 7, or hydroxyat position 5 or position 7.

More preferably R₆ is hydrogen, 4-methyl, 6-methyl or 7-methoxy.

R₇ is preferably at position 5, 6 or 7.

R₇ is preferably hydrogen or C₁-C₄-alkyl, such as, for example methyl ort-butyl. For example R₇ may be a C₁-C₄-alkyl at position 5, 6 or 7, suchas 5-methyl, 7-methyl or 6-t-butyl.

More preferably R₇ is hydrogen.

R₈ is preferably at position 6 or 7.

R₈ is preferably hydrogen, hydroxy or C₁-C₄-alkoxy, such as methoxy. Forexample, R₈ may be a C₁-C₄-alkoxy at position 6, such as 6-methoxy, or6-hydroxy or 7-hydroxy.

R₉ is preferably hydrogen or methyl.

When n=1 and m=0

R₁ is preferably hydrogen or methyl.

R₂, R₃, R₄, R₅ and R₉ are preferably hydrogen,

R₆ is preferably hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, such as,for example, methyl or t-butyl, methoxy or hydroxy. R₆ is preferably atposition 4, 5 or 6. For example, R₆ may be a C₁-C₄-alkyl at position 4,5 or 6, such as 4- or 5-methyl or 5-t-butyl or a C₁-C₄-alkoxy atposition 5 or 6, such as 5- or 6-methoxy, or 4-, 5- or 6-hydroxy. R₆ maybe halogen at position 5 or 6, such as 5- or 6-fluoro.

More preferably R₆ is 4-, 5- or 6-hydroxy.

R₇ is preferably at position 5, 6 or 7.

R₇ is preferably hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy or hydroxyl. Forexample, R₇ may be C₁-C₄-alkyl at position 5, 6 or 7, such as 5- or7-methyl or 5- or 6-t-butyl or C₁-C₄-alkoxy at position 6, such as6-methoxy, or 6-hydroxy.

More preferably R₇ is hydrogen or 6-hydroxy or 6-t-butyl.

R₈ is preferably at position 6 or 7.

R₈ is preferably hydrogen, hydroxy, C₁-C₄-alkyl, C₁-C₄-alkoxy, such asmethyl or methoxy, for example C₁-C₄-alkyl at position 7, such as7-methyl or 7-t-butyl or C₁-C₄-alkoxy at position 6, such as 6-methoxyor 6-hydroxy.

When n=m=1

R₁, R₂, R₃, R₅, R₈, R₉ and R₁₀ are preferably hydrogen.

R₄ is preferably hydrogen or C₁-C₄-alkyl, such as, for example, methyl.

R₆ is preferably at position 5, 6 or 7.

R₆ is preferably hydrogen, C₁-C₄-alkoxy or hydroxy, for example methoxy.For example, R₆ may be 5-, 6- or 7-methoxy, or 6- or 7-hydroxy.

R₇ is preferably hydrogen or C₁-C₄-alkyl, such as, for example, t-butyl.

When n=0 and m=1

R₃, R₄, R₅, R₇, R₈, R₉ and R₁₀ are preferably hydrogen.

R₆ is preferably hydrogen or halogeN, for example chlorine. R₆ may be ahalogen at position 5, such as, for example 5-chloro.

The invention includes within its scope all the possible isomers andstereoisomers, in particular Z and E (cis and trans isomers) andenantiomers.

The compounds of the formula (I) form acid addition salts with bothorganic and inorganic acids. Typical acid addition salts are chlorides,bromides, sulfates, nitrates, phosphates, sulfonates, formates,tartrates, maleates, citrates, benzoates, salicylates, ascorbates.Furthermore, compounds wherein one or more of R₄ to R₈ is a hydroxygroup form esters and salts with alkali metals and alkaline earthmetals. Typical esters include the lower alkyl esters, such as themethyl, ethyl and propyl esters.

The compounds of the invention may be prepared using the followingmethods. (It is to be noted that in the formulae below, when theimidazole group is protected, the protecting group R′ (benzyl or trityl)may be attached to either of the two nitrogen atoms of the imidazolering. Accordingly, the use of 1-benzyl-5-imidazolecarbaldehyde asstarting material leads to 1.5 substituted derivatives whereas whentrityl is used the substitution is mainly 1.4.)

Synthesis of 4(5)-(1-indanyl)imidazoles and the corresponding4(5)-[1-(1,2,3,4-tetrahydronaphthyl)]imidazoles

Method a

Compounds of formula I wherein n=0 and m=0 or 1 may be prepared by anacid catalyzed cyclization of protected or unprotected4(5)-(1-hydroxy-3-phenylpropyl or 1-hydroxy4-phenylbutyl)imidazoles offormulae II and II′, respectively.

Accordingly, the 4(5)-(1-indanyl)imidazoles may be prepared bycyclization of the compound of formula II

wherein R₃ to R₉ are as defined above and R′ is a protecting group, inthe presence of an acid to form the compounds of formula III

wherein the substituents are as defined above, and removing theprotecting group R′ to form the compounds of formula Ia

The corresponding 4(5)-[1-(1,2,3,4-tetrahydronaphthyl)]imidazoles may beprepared by cyclization of the compound of II′

wherein R₃ to R₁₀ are as defined above I and R′ is a protecting group inthe presence of an acid to form the compounds of formula III′

wherein the substituents are as defined above, and removing theprotecting group R′ to form the compounds of formula Ia′

wherein the substituents are as defined above.

The protecting group R′ may be, for example, benzyl or trityl. When R′is trityl it may be removed using an acid and, when it is benzyl, bycatalytic hydrogenation. The acid used in the cyclization reaction maybe, for example, polyphosphoric acid (PPA) or methanesulfonic acid.

The starting materials (compounds of the formulae II and II′,respectively) may be synthesized using different methods. One of them isto prepare α,β-unsaturated ketones through an aldol condensation byallowing an imidazolyl alkyl ketone to react with an appropriatelysubstituted benzaldehyde in the presence of a base:

The accompanying reduction of carbonyl and the following catalytichydrogenation produces saturated alcohols used in the cyclization. Thereduction of the carbonyl group may be performed for example with sodiumborohydride. If the imidazole moiety has been substituted with thebenzyl group it may also be removed by catalytic hydrogenation.

To accomplish substitution at the position 1 of the indane or1,2,3,4-tetrahydronaphthalene ring it is possible to carry out an1,2-addition reaction of the intermediate ketone with a nucleophilebefore the hydrogenation. This is conveniently perfomed through theGrignard reaction which is carried out by adding to the reaction mixturean alkyl magnesium halide, e.g. bromide, made from alkyl halide andmagnesium:

Another useful method to produce appropriate alcohols needed as startingmaterials in the cyclization is the use of the Grignard reaction in thepreparation of 4(5)-(1-hydroxy-phenylalkyl)imidazoles. Here the4(5)-imidazole carbaldehyde or ketone is allowed to react with aGrignard reagent, prepared from appropriately substituted phenylalkylhalide and magnesium:

Method b

To obtain substitution at the position 3 of the indane group thefollowing procedure may be used: An intermediate of formula Ib, which isalso an active compound wherein R₄ and R₅ together form a carbonylgroup, is prepared.

There are different methods for the preparation of this intermediate.

Firstly, it may be prepared using an acid catalyzed cyclization of1-aryl-3-[4(5)-imidazolyl]-α,β-unsaturated-1-propanones:

The α,β-unsaturated ketone used as the starting material in the abovereaction may be prepared by a base catalyzed aldol condensation fromsubstituted or unsubstituted 4(5)-imidazole carbaldehyde and fromappropriately substituted phenyl alkyl ketone.

Secondly, it may be prepared through the condensation of benzylprotected urocanic acid with an appropriately substituted benzene:

The benzyl protection is abolished by hydrogenation as describedearlier.

The ketone group may be then further modified using different methods.It may be reduced to the corresponding alcohol with sodium borohydrideor by catalytic hydrogenation, whereafter the alcohol may behydrogenated:

It is also possible to modify the ketone group using Grignard reaction:

These compounds may be further transformed to compounds of formula Iwherein n=m=0 and R₄ is an alkyl and R₅ is hydrogen by catalytichydrogenation as described above.

The compounds of formula Ib wherein R₄ is alkoxy and R₅ is hydrogen maybe prepared from the corresponding alcohol in concentrated hydrochloricacid.

Method c

A further method to synthesize the 4(5)-(1-indanyl)imidazoles of theformula I is to use the lithiated imidazole in an aromatic electrophilicsubstitution reaction with an 1-indanone (imidazole being bis-protectedaccording to the method described by Kudzma et al. in Synthesis, (1991),p. 1021). The protection may be removed by acid treatment, which inducesthe simultaneous loss of water. The double bond is reduced by catalytichydrogenation as described above.

Syntehesis of 4(5)-(indan-1-ylmethyl)imidazoles and4(5)-(indan-1-ylmethylen)imidazoles and the correspondingtetrahydronaphthyl derivatives

Method d

The preparation of 4(5)(indan-1-ylmethyl andindan-1-ylmethylen)imidazole and the corresponding tetrahydronaphthylskeleton may be accomplished using the so called McMurry reaction, inwhich an imidazole carbaldehyde or ketone reacts with an 1-indanone. Thereaction is catalyzed by low valence titanium. The condensation may befollowed by the hydrogenation of the double bond and simultaneouselimination of the protecting group in the imidazole ring.

The compounds of the invention may be administered enterally, topicallyor parenterally. Parenteral administration is used, for example, whenthe compounds are given as sedative or anxiolytic agents in connectionto different clinical operations and to cause analgesia or to potentiateanesthesia.

The compounds of the invention may be formulated alone or together withanother active ingredient and/or a pharmaceutically acceptable diluentor carrier to different pharmaceutical unit dosage forms i.e. tablets,capsules, solutions, emulsions and powders etc. using conventionaltechniques. The pharmaceutical carriers employed are selected with theplanned manner of administration in mind. Thus, solid carriers mayinclude lactose, sucrose, gelatin and agar, while liquid carrierstypically include waters syrup, peanut oil and olive oil. The amount ofthe active ingredient varies from 0.01 to 75 weight-% depending on thetype of the dosage form.

The appropriate oral dosage for the compounds of the invention dependson several factors such as the compound to be administrated, thespecies, age and the sex of the subject to be treated, the condition tobe treated and on the method of administration. Accordingly, the dosagefor parenteral administration is typically from 0.5 μg/kg to 10 mg/kgper day and that for oral administration is from 5 μg/kg to 100 mg/kgfor an adult male.

The invention also provides a compound of the invention or an ester orsalt thereof for use in a method of treatment of human or animal body.

The present invention further provides a compound of the invention or anester or salt thereof for use in the treatment of hypertension,glaucoma, chronic and acute pain, migraine, diarrhea, common cold,ischemia, addiction to chemical substances, anxiety, especiallypreoperative anxiety and different neurological, musculoskeletal,psychiatric and cognition disorders or as an adjunct to anesthesia.

The invention also provides the use of a compound of the invention or anester or salt thereof in the manufacture of a medicament for thetreatment of hypertension, glaucoma, chronic and acute pain, migraine,diarrhea, common cold, ischemia, addiction to chemical substances,anxiety, especially preoperative anxiety and different neurological,musculoskeletal, psychiatric and cognition disorders or as an adjunct toanesthesia.

The invention further relates to a method for the treatment ofhypertension, glaucoma, chronic and acute pain, migraine, diarrhea,common cold, ischemia, addiction to chemical substances, anxiety,especially preoperative anxiety and different neurological,musculoskeletal, psychiatric and cognition disorders by administering toa subject in need of such treatment an effective amount of the compoundof the invention or a pharmaceutically acceptable ester or salt thereof.

Test Results

1. Alpha2 agonism in rat vas deferens model

Alpha2 agonism was determined by means of isolated, electricallystimulated prostatic portions of rat vas deferens preparation (Virtanenet al. Arch. Int. Pharmacodyn et Ther. 297 (1989), pp. 190-204). In thismodel, an alpha2 agonist is able to inhibit electrically inducedmuscular contractions by activating the presynaptic alpha2 adrenoceptorsand thus diminishing the secretion on the motor transmitter. The knownalpha2 agonist dexmedetomidine was used as reference substance. Resultsare shown in Table 1, where the alpha2 agonist effect is presented asthe pD₂-value (negative logarithm of the molar concentration of thecompound producing 50 percent of maximal inhibition).

The following compounds were tested:

1 4-(4-Methylindan-1-yl)-1H-imidazole hydrochloride

2 3-(1H-Imidazol-4-ylmethyl)-indan-5-ol hydrochloride

3 4-[1-(Indan-1-yl)-ethyl]-1H-imidazole hydrochloride

4 8-(1H-Imidazol-4-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-olhydrochloride

5 dexmedetomidine (reference compound)

TABLE 1 Alpha2 agonism in vitro Compound pD₂-value 1 8.1 + −0.2 2 8.5 +−0.1 3 8.9 + −0.3 4 7.0 + −0.1 5 8.4 + −0.1

2. Binding assays

Affinities for α₂-adrenoceptors and α₁-adrenoceptors were estimated bydetermining the displacement of 1 nM ³H-RX821002 (α₂) or 0.1 nM³H-prazosin (α₁) from α-adrenoceptors in rat neocortical membranes. Forthis purpose membranes were incubated with different concentrations oftest compounds spanning a concentration range of five orders ofmagnitude. Nonspecific binding was defined with 10 μM phentolamine.Membranes were used at a protein concentration of 2 mg/ml in a totalvolume of 250 μl. The incubation buffer consisted of 50 mM TRIS-HCl, pH7.7. After a 30 min incubation at 25° C. samples were filtered throughglass fibre filter and filters were washed three times with 4 ml icecoldwash buffer consisting of 10 mM TRIS-HCl, pH 7.7. Filters were thendried, impregnated with a scintillation cocktail and counted in ascintillation counter. Experimental data was analyzed using thecommercial nonlinear least squares computer program LIGAND.

Each compound was tested in at least three independent experiments forits affinity on rat neocortical α₂- or α₁-adrenoceptors. The results areshown in Table 2.

TABLE 2 Affinity on rat neocortical α₂- or α₁-adrenoceptors alpha2 vsalpha1 Compound pKi α₂ pKi α₁ selectivity 1 8.44 7.31 14 2 8.70 6.61 1263 8.35 6.21 142 4 7.39 6.85 3 5 8.42 6.48 90

The following examples illustrate how compounds of the invention may beprepared.

EXAMPLES

4-(6-tert-Butylindan-1-yl)-1H-imidazole

a) 3-(4-tert-Butylphenyl)-1-(1H-imidazol-4-yl)-propan-1-ol

A solution of 4-tert-butylbenzaldehyde (5.7 g),1-(3-benzyl-3H-imidazol4-yl)-ethanone (7.0 g) and 48% sodium hydroxide(2.0 ml) in methanol (60 ml) is heated at 60-65° C. for 11 hours. Thereaction mixture is then cooled in an ice bath. The resultingprecipitate is filtered and the solid intermediate1-(3-benzyl-3H-imidazol-4-yl)-3-(4-tert-butylphenyl)-propen-1-one isrinsed with methanol. The yield is 10.0 g.

The intermediate is dissolved in the mixture of ethanol (170 ml) andconcentrated hydrochloric acid (3 ml). The reaction mixture ishydrogenated at 50-60° C. with 10% palladium on carbon as catalyst untilno more hydrogen is consumed. The mixture is filtered and the filtrateis evaporated to dryness. The residue is dissolved in water and is madealkaline with sodium hydroxide. The product is then extracted intomethylene chloride which is washed with water, dried with sodium sulfateand evaporated to dryness. The product is converted to its hydrochloridesalt in ethyl acetate using dry hydrochloric acid. The yield is 6.8 g.

¹H NMR (as HCl-salt, MeOH-d₄): 1.29 (s, 9H), 2.06-2.13 (m, 2H),2.62-2.78 (m, 2H), 4.77 (t, 1H), 7.13 (m, 2H), 7.30 (m, 2H), 7.40 (s,1H), 8.79 (s, 1H)

b) 4-(6-tert-Butylindan-1-yl)-1H-imidazole

A mixture of 3-(4-tert-butylphenyl)-1-(1H-imidazol4-yl)-propan-1-ol (2.0g) and methanesulfonic acid (30 ml) is heated at 60° C. for 5 minutes.The reaction is then quenched by pouring it into ice-water solution. Theacidic solution is made basic with ammmonium hydroxide solution, andextracted with ethyl acetate. The combined organic layers are washedwith water, dried with sodium sulfate, and evaporated to dryness underreduced pressure. The crude product is purified by flash chromatographyby eluting with methylene chloride-methanol as eluent. The product iscrystallized from ethyl acetate. The yield is 220 mg.

¹H NMR (MeOH-d₄); 1.24 (s, 9H), 2.07-2.20 (m, 1H), 2.43-2.54 (m, 1H),2.81-3.01 (m, 2H), 4.35 (t, 1H), 6.74 (s, 1H), 7.09 (s, 1H), 7.14-7.21(m, 2H), 7.60 (s, 1H)

Using the same method the following compounds were prepared:

4-(Indan-1-yl)-1H-imidazole

¹H NMR (CDCl₃) 2.08-2.19 (m, 1H), 2.41-2.51 (m, 1H), 2.80-2.95 (m, 2H),4.37 (t, 1H), 6.65 (s, 1H), 7.07-7.21 (m, 4H); 7.25 (s, 1H)

4-(4-Methylindan-1-yl)-1H-imidazole. M.p. of hydrochloride 153-156° C.

¹ H NMR (as HCl-salt, MeOH-d₄): 2.08-2.20 (m, 1H), 2.30 (s, 3H),2.58-2.69 (m, 1H), 2.87-3.10 (m, 2H), 4.59 (t, 1H), 6.89 (d, J=7.0 Hz,1H), 7.05-7.13 (m, 2H), 7.30 (s, 1H), 8.83 (s, 1H)

4-(6-Methylindan-1-yl)-1H-imidazole

¹H NMR (as HCl-salt, MeOH-d₄): 2.07-2.20 (m, 1H), 2.28 (s, 3H),2.55-2.66 (m, 1H), 2.89-3.08 (m, 2H), 4.53 (t, 1H), 6.88 (s, 1H), 7.06(d, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.30 (s, 1H), 8.79 (s, 1H)

4-(6-Ethylindan-1-yl)-1H-imidazole

¹H NMR (as HCl-salt, MeOH-d₄): 1.17 (t, 3H), 2.08-2.21 (m, 1H),2.55-2.67 (m, 3H), 2.90-3.10 (m, 2H), 4.56 (t, 1H), 6.91 (s, 1H), 7.08(d, J=7.7 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.32 (s, 1H), 8.85 (s, 1H)

4-(4,5-Dimethylindan-1-yl)-1H-imidazole. M.p of hydrochloride 161-164°C.

¹H NMR (as HCl-salt, MeOH-d₄) 2.06-2.18 (m, 1H), 2.22 (s, 3H), 2.26 (s,3H), 2.56-2.68 (m, 1H), 2.87-3.11 (m, 2H), 4.55 (t, 1H), 6.78 (d, J=7.6Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 7.27 (s, 1H), 8.80 (s, 1H)

4-(5,7-Dimethylindan-1-yl)-1H-imidazole

¹H NMR (CDCl₃); 2.07 (s, 3H), 2.07-2.22 (m, 1H), 2.31 (s, 3H), 2.40-2.53(m, 1H), 2.77-2.87 (m, 1H), 2.94-3.05 (m, 1H), 4.44 (m, 1H), 6.55 (s,1H), 6.80 (s, 1H), 6.94 (s, 1H), 7.53 (s, 1H)

4-(2,4-Dimethylindan-1-yl)-1H-imidazole

¹H NMR (CDCl₃): 1.23 (d, 3H), 2.28 (s, 3H), 2.46-2.55 (m, 2H), 3.05-3.16(m, 1H), 3.92 (d, 1H), 6.81-6.83 (m, 2H), 6.95-7.09 (m, 2H), 7.56 (s,1H)

4-(5-Methoxyindan-1-yl)-1H-imidazole. M.p. 180-184° C.

¹H NMR (CDCl₃+MeOH-d₄); 2.09-2.19 (m, 1H), 2.48-2.59 (m, 1H), 2.87-2.98(m, 2H), 3.79 (s, 3H), 4.35 (t, 1H), 6.69-6.73 (m, 2H), 6.82 (d, J=2.0Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 7.53 (s, 1H)

4-(7-Methoxyindan-1-yl)-1H-imidazole

¹H NMR (CDCl₃); 2.20-2.50 (m, 2H), 2.83-2.98 (m, 2H), 3.82 (s, 3H),4.50-4.54 (m, 1H), 6.66-6.72 (m, 2H), 6.86 (d, J=7.7 Hz, 1H), 7.16 (t,J=7.7 Hz, 1H), 7.43 (s, 1H)

EXAMPLE 2

4-(1-Methylindan-1-yl)-1H-imidazole

a) 2-(3-Benzyl-3H-imidazol-4-yl)4-phenylbutan-2-ol

1.0 g of magnesium turnings are covered with 5 ml of drytetrahydrofuran. To the mixture is added 7.8 g of (2-bromoethyl)benzenein 30 ml of dry tetrahydrofuran at such a rate that a smooth reaction ismaintained. The mixture is then heated under reflux for one hour. Afterbeing cooled to room temperature, 3.0 g of1-(3-benzyl-3H-imidazol-4-yl)-ethanone in 20 ml of tetrahyrofuran isadded dropwise to the Grignard reagent and the reaction mixture isrefluxed for one hour. The cooled reaction mixture is poured into a colddilute hydrochloric acid solution. Work-up of the mixture gives thecrude product, which is recrystallized from ethyl acetate. The yield is3.3 g.

¹H NMR (as HCl-salt, MeOH-d₄): 1.67 (s, 3H), 2.01-2.08 (m, 2H),2.37-2.48 (m, 1H), 2.57-2.71 (m, 1H), 5.75 (dd, 2H), 6.97-7.42 (m, 10H),7.50 (s, 1H), 8.75 (s, 1H)

b) 2-(1H-Imidazol-4-yl)4-phenylbutan-2-ol

3.3 g of 2-(3-benzyl-3H-imidazol-4-yl)-4-phenylbutan-2-ol is dissolvedin 100 ml of ethanol. The reaction solution is hydrogenated at 50° C.with 10% palladium on carbon as catalyst for 4.5 hours. Work-up of thereaction mixture gives the crude product, which is recrystallized fromethyl acetate. The yield is 2.0 g.

¹H NMR (MeOH-d₄): 1.56 (s, 3H), 2.01-2.13 (m, 2H), 2.37-2.47 (m, 1H),2.53-2.64 (m, 1H), 6.96 (s, 1H), 7.07-7.13 (m, 3H), 7.18-7.23 (m, 2H),7.61 (s, 1H)

c) 4-(1-Methylindan-1-yl)-1H-imidazole

A mixture of 2-(1H-imidazol-2-yl)-4-phenylbutan-2-ol (0.5 g) andmethanesulfonic acid (12 ml) is heated at 100° C. for 35 minutes. Thecooled reaction mixture is poured into water and is made alkaline withsodium hydroxide solution. The product is extracted into ethyl acetatewhich is washed with water, dried with sodium sulfate and evaporatedunder reduced pressure. The product is converted to its hydrochloridesalt in ethyl acetate using dry hydrochloric acid. The yield is 387 mg,m.p. 164-171° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.67 (s, 3H), 2.21-2.30 (m, 1H),2.40-2.50 (m, 1H), 2.96-3.11 (m, 2H), 7.06-7.33 (m, 5H), 8.84 (s, 1H)

EXAMPLE 3

4-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazole

a) 4-(2-Chlorophenyl)-1-(1H-imidazol-4-yl)-butan-1-ol

3.3 g of magnesium turnings are covered with 40 ml of drytetrahydrofuran. To the mixture is added 32.0 g of1-(3-bromopropyl)-2-chlorobenzene (prepared according to Baddar, F. G.et al., J. Chem. Soc., 1959, 1027) in 100 ml of dry tetrahydrofuran atsuch a rate that a smooth reaction is maintained. When the magnesiumturnings have reacted the solution is cooled to room temperature. 4.3 gof imidazole-4-carbaldehyde in 40 ml of dry tetrahydrofuran is thenadded dropwise to the Grignard reagent and the reaction mixture isrefluxed for one hour. The cooled reaction mixture is poured into a colddilute hydrochloric acid solution. Tetrahydrofuran is distilled offunder reduced pressure and the residue is cooled. The resultingprecipitate is filtered and washed with water. The crude product isrecrystallized from ethanol. The yield is 8.0 g. Melting point of thehydrochloride salt is 152-154° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.65-1.91 (m, 4H), 2.80 (t, 2H), 4.82,(t, 1H), 7.14-7.35 (m, 4H), 7.40 (s, 1H), 8.83 (s, 1H)

b) 4-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazole

A mixture of 4-(2-chlorophenyl)-1-(1H-imidazol-4-yl)-butan-1-olhydrochloride (1.0 g) and methanesulfonic acid (15 ml) is heated at 100°C. for 2 hours. The cooled reaction mixture is poured into water and ismade alkaline with sodium hydroxide solution. The product is extractedinto ethyl acetate which is washed with water, dried with sodium sulfateand evaporated under reduced pressure. The crude product isrecrystallized from ethyl acetate. The yield is 0.4 g, m.p. 165-169° C.

¹H NMR (CDCl₃): 1.74-1.83 (m, 2H), 1.95-2.15 (m, 2H), 2.70-2.91 (m, 2H),4.19 (t, 1H), 6.49 (s, 1H), 6.96-7.05 (m, 2H), 7.21-7.24 (m, 1H), 7.54(s, 1H)

EXAMPLE 4

4-(1,2,3,4-Tetrahydronaphthalen-1-yl)-1H-imidazole

4-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazole (300 mg) isdissolved in ethanol (15 ml). The reaction solution is hydrogenated at50° C. with 10% palladium on carbon as catalyst for 8 hours. The mixtureis filtered to remove the catalyst, and the filtrate is evaporated underreduced pressure. The residue is dissolved in water and is made alkalinewith sodium hydroxide solution. The product is extracted into methylenechloride which is washed with water, dried with sodium sulfate andevaporated under reduced pressure. The crude product is recrystallizedfrom ethyl acetate. The yield is 169 mg, m.p. 105-110° C.

¹H NMR (CDCl₃): 1.70-1.85 (m, 2H), 2.05-2.11 (m, 2H), 2.78-2.86 (m, 2H),4.21 (t, 1H), 6.59 (s, 1H), 7.04-7.14 (m, 4H), 7.52 (s, 1H)

EXAMPLE 5

3-(1H-Imidazol4-yl)-5-isobutylindan-1-ol

a) 3-(3-Benzyl-3H-imidazol-4-yl)-1-(4-isobutylphenyl)-propen-1-one

A solution of 4-isobutylacetophenone (2.0 g),3-benzyl-3H-imidazole-4-carbaldehyde (2.1 g) and 48% sodium hydroxide(0.65 ml) in methanol (20 ml) is heated at 55-60° C. for 6 hours. Thereaction mixture is then cooled in an ice bath. The resultingprecipitate is filtered, and rinsed with methanol. The yield is 2.5 g.

¹H NMR (CDCl₃): 0.91 (d, 6H), 1.85-1.95 (m, 1H), 2.54 (d, 2H), 5.28 (s,2H), 7.12-7.14 (m, 2H), 7.23 (d, J=8.2 Hz, 2H), 7.30-7.41 (m, 4H),7.60-7.68 (m, 3H), 7.80 (d, J=8.2 Hz, 2H)

b) 3-(3-Benzyl-3H-imidazol-4-yl)-5-isobutylindan-1-one

A mixture of3-(3-benzyl-3H-imidazol-4-yl)-1-(4-isobutylphenyl)-propen-1-one (2.4 g)and methanesulfonic acid (40 ml) is heated at 120° C. for 40 minutes.Work-up of the reaction mixture gives the crude product, which ispurified by flash chromatography by eluting with methylenechloride-methanol solution. The yield is 0.5 g.

¹H NMR (CDCl₃): 0.89 (d, 6H), 1.81-1.91 (m, 1H), 2.34 (dd, J=18.8 Hz,J=4.0 Hz, 1H), 2.51 (d, 2H), 2.80 (dd, J=18.8 Hz, J=7.9 Hz, 1H),4.44-4.48 (m, 1H), 5.03-5.16 (m, 2H), 6.64 (s, 1H), 7.05-7.08 (m, 2H),7.13 (s, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.26-7.39 (m, 3H), 7.57 (s, 1H),7.68 (d, J=7.8 Hz, 1H)

c) 3-(1H-Imidazol-4-yl)-5-isobutylindan-1-ol

3-(3-Benzyl-3H-imidazol-4-yl)-5-isobutylindan-1-one (0.5 g) is dissolvedin ethanol (15 ml). The reaction solution is hydrogenated at 50° C. with10% palladium on carbon as catalyst until no more hydrogen is consumed.The mixture is filtered to remove the catalyst, and the filtrate isevaporated under reduced pressure. The crude product contains cis- andtrans-isomers. The isomers are purified by flash chromatography.

¹H NMR (cis-isomer, CDCl₃): 0.85 (d, 6H), 1.74-1.84(m, 1H), 2.15-2.20(m, 1H), 2.40 (d, 2H), 2.69-2.79 (m, 1H), 4.33 (d, 1H), 5.16 (d, 1H),6.91 (s, 1H), 6.93 (s, 1H), 7.02 (d, J=7.7 Hz, 1H), 7.39 (d, J=7.7 Hz,1H), 7.42 (s, 1H) ¹H NMR (trans-isomer, CDCl₃): 0.85 (d, 6H), 1.74-1.84(m, 1H), 2.35-2.46 (m, 4H), 4.60 (t, 1H), 5.26 (t, ₁H), 6.65 (s, 1H),6.95 (s, 1H), 7.04 (d, J=7.7 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 7.46 (s,1H)

EXAMPLE 6

3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one

a) 3-(3-Benzyl-3H-imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one

A mixture of 2,3-dimethylanisole (2.0 g),3-(3-benzyl-3H-imidazol-4-yl)-acrylic acid (3.4 g) and methanesulfonicacid (60 ml) is heated at 90-95° C. for 45 minutes.The cooled reactionmixture is poured into water and is made alkaline with sodium hydroxidesolution. The product is extracted into ethyl acetate which is washedwith water, dried with sodium sulfate and evaporated in reducedpressure. The crude product is purified by flash chromatography byeluting with methylene chloride-methanol solution. The yield is 1.1 g.

¹H NMR (CDCl₃): 2.13 (s, 3H), 2.35 (dd, J=18.5 Hz, J=4.1 Hz, 1H), 2.61(s, 3H), 2.81 (dd, J=18.5 Hz, J=8.2 Hz, 1H), 3.76 (s, 3H), 4.34-4.38 (m,1H), 5.05 (s, 2H), 6.52 (s, 1H), 6.72 (s, 1H), 7.00-7.05 (m, 2H),7.29-7.36 (m, 3H), 7.56 (s, 1H)

b) 3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one

3-(3-Benzyl-3H-imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one (1.1 g)is dissolved in ethanol (90 ml). The reaction solution is hydrogenatedat 50-55° C. with 10% palladium on carbon as catalyst for 7 hours. Themixture is filtered to remove the catalyst, and the filtrate isevaporated under reduced pressure. The product is converted to itshydrochloride salt in ethyl acetate using dry hydrochloric acid. Theyield is 0.6 g, m.p. 258-261° C.

¹H NMR (as HCl-salt, MeOH-d₄): 2.16 (s, 3H), 2.62 (s, 3H), 2.68 (dd,J=18.7 Hz, J=4.0 Hz, 1H), 3.18 (dd, J=18.7 Hz, J=8.3 Hz, 1H), 3.87 (s,3H), 4.77-4.81 (m, 1H), 6.81 (s, 1H), 7.43 (s, 1H), 8.85 (s, 1H)

Using the same method the following compound was prepared:

3-(1H-Imidazol-4-yl)-5-methoxy-4,7-dimethylindan-1-one

¹H NMR (CDCl₃): 1.96 (s, 3H), 2.64 (dd, J=18.6 Hz, J=2.1 Hz, 1H), 2.65(s, 3H), 3.13 (dd, J=18.6 Hz, J=8.4 Hz, 1H), 3.90 (s, 3H), 4.57-4.61 (m,1H), 6.47 (s, 1H), 6.68 (s, 1H), 7.50 (s, 1H)

EXAMPLE 7

3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-ol

3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one (0.53 g) isdissolved in ethanol (30 ml) and 0.3 g of sodium borohydride is added.The mixture is stirred at 35-40° C. for 7 hours. About 20 ml of ethanolis then distilled off and 30 ml of water is added. The solution isextracted with ethyl acetate. The combined ethyl acetate extracts arewashed with water, dried with sodium sulfate, and evaporated underreduced pressure. The product is the mixture of cis- and trans-isomers(about 85:15). Crystallization of the product from ethyl acetate gives acis-isomer, m.p. 184-189° C.

¹H NMR (cis-isomer, CDCl₃): 2.09-2.14 (m, 1H), 2.11 (s, 3H), 2.38 (s,3H), 2.69-2.77 (m, 1H), 3.73 (s, 3H), 4.31 (d, 1H), 5.26 (d, 1H), 6.48(s, 1H), 6.90 (s, 1H), 7.43 (s, 1H)

EXAMPLE 8

4-(6-Methoxy-4,5-dimethylindan-1-yl)-1H-imidazole

3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-ol (0.29 g) isdissolved in the mixture of ethanol (30 ml) and concentratedhydrochloric acid (0.2 ml). The solution is hydrogenated at 50-55° C.with 10% palladium on carbon as catalyst until no more hydrogen isconsumed. The mixture is filtered and the filtrate is evaporated todryness. The residue is crystallized from the mixture of ethyl acetateand ethanol. M.p. of the hydrochloride salt is 174-177° C.

¹H NMR (as HCl-salt, MeOH-d₄): 2.05-2.17 (m, 1H), 2.11 (s, 3H), 2.21 (s,3H), 2.54-2.66 (m, 1H), 2.82-3.05 (m, 2H), 3.71 (s, 3H), 4.55 (t, 1H),6.50 (s, 1H), 7.27 (s, 1H), 8.79 (s, 1H)

Using the same method the following compound was prepared:

4-(6-Isobutylindan-1-yl)-1H-imidazole

¹H NMR (as HCl-salt, MeOH-d₄): 0.86 (d, 6H), 1.73-1.83 (m, 1H),2.11-2.18 (m, 1H), 2.42 (d, 2H), 2.58-2.65 (m, 1H), 2.97-3.31 (m, 2H),4.56 (t, 1H), 6.85 (s, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.22 (d, J=7.6 Hz,1H), 7.30 (s, 1H), 8.83 (s, 1H)

EXAMPLE 9

3-(1H-imidazol-4-yl)-6,7-dimethylindan-5-ol

A stirred mixture of 4-(6-methoxy-4,5-dimethylindan-1-yl)-1H-imidazolehydrochloride (0.29 g) and hydrobromic acid (15 ml) is heated underreflux for 40 minutes. The cooled reaction mixture is poured into waterand is made basic with ammonium hydroxide solution. The product isextracted into ethyl acetate which is washed with water, dried withsodium sulfate and evaporated to dryness. The crude product is purifiedby flash chromatography and crystallized from ethyl acetate. M.p.198-202° C.

¹H NMR (CDCl₃+MeOH-d₄): 2.02-2.13 (m, 1H), 2.13 (s, 3H), 2.18 (s, 3H),2.43-2.54 (m, 1H), 2.71-2.82 (m, 1H), 2.86-2.96 (m, 1H), 4.33 (t, 1H),6.49 (s, 1H), 6.75 (s, 1H), 7.50 (s, 1H)

Using the same method the following compound was prepared:

5-Hydroxy-3-(1H-imidazol-4-yl)-6,7-dimethylindan-1-one

¹H NMR (MeOH-d₄): 2.12 (s, 3H), 2.58 (s, 3H), 2.67 (dd, J=18.4 Hz, J=4.1Hz, 1H), 3.02 (dd, J=18.4 Hz, J=8.0 Hz, 1H), 4.43-4.47 (m, 1H), 6.59 (s,1H), 6.90 (s, 1H), 7.62 (s, 1H)

1-(1H-Imidazol-4-yl)-indan5-ol. M.p. 210-220° C.

¹H NMR(MeOH-d₄): 2.04-2.17 (m, 1H), 2.41-2.52(m, 1H), 2.77-2.97 (m, 2H),4.27 (t, 1H), 6.55 (dd, J=8.1 Hz, J=2.3 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H),6.70 (s, 1H), 6.84 (d, J=8.1 Hz, 1H), 7.57 (s, 1H)

3-(1H-imidazol-4-yl)-indan-4-ol. M.p. 142-145° C.

¹H NMR (CDCl₃+MeOH-d₄): 2.13-2.26 (m, 1H), 2.49-2.60 (m, 1H). 2.89-3.08(m, 2H), 4.54 (t, 1H), 6.71-6.76 (m, 3H), 7.06 (t, J=7.6 Hz, 1H), 7.55(s, 1H)

EXAMPLE 10

4-(3-Ethoxy-6-methoxy4,5-dimethylindan-1-yl)- 1H-imidazole (cis-isomer)

3-(1H-Imidazol4-yl)-5-methoxy-6,7-dimethylindan-1-ol (cis-isomer, 0.1 g)is dissolved in the mixture of ethanol (20 ml) and concentratedhydrochloric acid (2 ml). The solution is stirred at 25° C. for onehour. Work-up of the reaction mixture gives the crude product, which ispurified by flash chromatography using methylene chloride-methanol aseluent.

¹H NMR (CDCl₃): 1.31 (t, J=7.0 Hz, 3H), 2.12 (s, 3H), 2.20-2.25 (m, 1H),2.32 (s, 3H), 2.51-2.60 (m, 1H), 3.72 (q, J=7.0 Hz, 2H), 3.73 (s, 3H),4.40 (d, 1H), 4.96 (d, 1H), 6.52 (s, 1H), 6.93 (s, 1H), 7.41 (s, 1H)

EXAMPLE 11

4-(Indan-1-yl)-1H-imidazole

a) 4-(3H-Inden-1-yl)-1H-imidazole

To a stirred solution of 1-(N,N-dimethylsulfamoyl)-1H-imidazole (1.9 g,prepared according to Chadwick, D. J. and Ngochindo, R. I., J. Chem.Soc., Perkin Trans. (1984, 481) in dry tetrahydrofuran (90 ml) at −70°C. under nitrogen, is added dropwise 2.5 M butyllithium in hexane (5.1ml). After 30 minutes tert-butyldimethylsilyl chloride (2.0 g) in drytetrahydrofuran (5 ml) is added and the mixture is allowed to warm to25° C. After 1.5 hours the mixture is again cooled to −70° C. andtreated with 2.5 M butyllithium in hexane (5.3 ml). After 30 minutes,1-indanone (2.1 g) in dry tetrahydrofuran (5 ml) is added and themixture is allowed to warm to room temperature. The reaction mixture isthen quenched with saturated Na₂CO₃ solution (2 ml), and the solvent isremoved under reduced pressure. The residue is dissolved in methylenechloride and washed with water, dried with sodium sufate and evaporatedto dryness under reduced pressure. The bis-protected intermediate isrefluxed with 2 N hydrochloric acid (200 ml) for 2 hours. The cooledsolution is made basic by ammonium hydroxide solution, and extractedwith methylene chloride. The organic layer is washed with water, driedwith sodium sulfate and the solvent removed under reduced pressure. Thecrude product is purified by flash chromatography using methylenechloride-methanol as eluent. The product is converted to thehydrochloride salt in ethyl acetate-ethanol solution, m.p. 232-240° C.

¹H NMR (as HCl-salt, MeOH-d₄); 3.66 (d, 2H), 7.07 (t, 1H), 7.31-7.43 (m,2H), 7.59 (d, 1H), 7.68 (d, 1H), 8.03 (s, 1H), 9.06 (s, 1H)

b) 4-(Indan-1-yl)-1H-imidazole

4-(3H-Inden-1-yl)-1H-imidazole hydrochloride (80 mg) is dissolved inethanol (6 ml). The reaction solution is hydrogenated at 40-50° C. with10% palladium on carbon as catalyst until no more hydrogen is consumed.Work-up of the reaction mixture gives the crude product which ispurified by flash chromatography using methylene chloride-methanol aseluent.

¹H NMR (CDCl₃): 2.08-2.19 (m, 1H), 2.41-2.51 (m, 1H), 2.80-2.95 (m, 2H),4.37 (t, 1H), 6.65 (s, 1H), 7.07-7.21 (m, 4H), 7.25 (s, 1H)

Using the same method the following compound was prepared:

4-(6-Methoxyindan-1-yl)-1H-imidazole

¹H NMR (as HCl-salt, MeOH-d₄); 2.08-2.20 (m, 1H), 2.56-2.67 (m, 1H),2.80-2.97 (m, 2H), 3.72 (s, 3H), 4.53 (t, 1H), 6.71 (d, J=1.9 Hz, 1H),6.75 (dd, J=8.3 Hz, J=1.9 Hz, 1H), 6.92 (s, 1H), 7.15 (d, J=83 Hz, 1H),8.82 (s, 1H)

EXAMPLE 12

4-(Indan-1-ylmethyl)-1H-imidazole

Titanium tetrachloride (17.2 g) is added dropwise to a stirredsuspension of zinc powder (11.9 g) in tetrahydrofuran (100 ml) with icecooling under a nitrogen atmosphere. The mixture is heated at reflux forone hour. After being cooled to room temperature, 1-indanone (2.0 g) and3-benzyl-3H-imidazole-4-carbaldehyde (4.2 g) in tetrahydrofuran (30 ml)are added into the mixture. The mixture is refluxed with stirring for 3hours. The cooled reaction mixture is made alkaline with dilute sodiumhydroxide solution. The slurry is filtered, and the filtratate isevaporated to dryness under reduced pressure. The residue, whichcontains the crude intermediate1-benzyl-5-(indan-1-ylidenemethyl)-1H-imidazole is purified by flashchromatography.

The purified intermediate (0.8 g) is dissolved in the mixture of ethanol(30 ml), water (2 ml) and concentrated hydrochloric acid (0.5 ml). Thereaction mixture is hydrogenated at 50-60° C. with 10% palladium oncarbon as catalyst until no more hydrogen is consumed. The mixture isfiltered, and the filtrate is evaporated to dryness. The residue isdissolved in water and is made alkaline with sodium hydroxide. Theproduct is then extracted into methylene chloride which is washed withwater, dried with sodium sulfate and evaporated to dryness. The productis converted to its hydrochloride salt in ethyl acetate using dryhydrochloric acid. The yield is 0.5 g, m.p. 182-183° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.74-1.81 (m, 1H), 2.22-2.29 (m, 1H),2.80-2.95 (m, 3H), 3.17 (dd, J=15.1 Hz, J=5.7 Hz, 1H), 3.48-3.53 (m,1H), 7.12-7.23 (m, 4H), 7.26 (s, 1H), 8.79 (s, 1H).

Using the same method the following compounds were prepared:

4-(6-Methoxyindan-1-ylmethyl)-1H-imidazole. M.p. of hydrochloride197-200° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.72-1.84 (m, 1H), 2.19-2.31 (m, 1H),2.70-2.89 (m, 3H), 3.16 (dd, J=14.9 Hz, J=5.5 Hz, 1H), 3.42-3.51 (m,1H), 3.74 (s, 3H), 6.68 (d, J=2.2 Hz, 1H), 6.74 (dd, J=8.2 Hz, J=2.2 Hz,1H), 7.10 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 8.82 (s, 1H)

4-(5-Methoxyindan-1-ylmethyl)-1H-imidazole. M.p. of hydrochloride204-206° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.71-1.83 (m, 1H), 2.19-2.31 (m, 1H),2.75-2.94 (m, 3H), 3.13 (dd, J=15.0 Hz, J=5.5 Hz, 1H), 3.40-3.49 (m,1H), 3.75 (s, 3H), 6.70 (dd, J=8.3 Hz, J=2.2 Hz, 1H), 6.78 (d, J=2.2 Hz,1H), 7.00 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 8.82 (s, 1H)

4-(5,6-Dimethoxyindan-1-ylmethyl)-1H-imidazole. M.p. of hydrochloride193-197° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.72-1.84 (m, 1H), 2.20-2.32 (m, 1H),2.75-2.88 (m, 3H), 3.15 (dd, J=15.1 Hz, J=5.2 Hz, 1H), 3.41-3.50 (m,1H), 3.77 (s, 3H), 3.79 (s, 3H), 6.73 (s, 1H), 6.84 (s, 1H), 7.26 (s,1H), 8.82 (s, 1H)

4-(6-Methoxy-4,5-dimethylindan-1-ylmethyl)-1H-imidazole. M.p. ofhydrochloride 194-197° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.70-1.81 (m, 1H), 2.09 (s, 3H), 2.15 (s,3H), 2.17-2.29 (m, 1H), 2.69-2.89 (m, 3H), 3.14 (dd, J=15.1 Hz, J=5.7Hz, 1H), 3.42-3.50 (m, 1H), 3.74 (s, 3H), 6.54 (s, 1H), 7.24 (s, 1H),8.81 (s, 1H)

4-(6-Methoxy-4,7-dimethylindan-1-ylmethyl)-1H-imidazole. M.p. ofhydrochloride 168-175° C.

¹H NMR (as HCl-salt, MeOH-d₄); 1.88-1.94 (m, 1H), 2.07 (s, 3H),2.09-2.18 (m, 1H), 2.19 (s, 3H), 2.69-2.77 (m, 3H), 2.90 (dd, J=15.2 Hz,J=4.7 Hz, 1H), 3.51-3.57 (m, 1H), 3.77 (s, 3H), 6.60 (s, 1H), 7.21 (s,1H), 8.80 (s, 1H)

4-(6-Methoxy-5-methylindan-1-ylmethyl)-1H-imidazole. M.p. ofhydrochloride 183-186° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.71-1.82 (m, 1H), 2.13 (s, 3H),2.18-2.29 (m, 1H), 2.70-2.89 (m, 3H), 3.16 (dd, J=15.0 Hz, J=5.4 Hz,1H), 3.42-3.50 (m, 1H), 3.76 (s, 3H), 6.65 (s, 1H), 6.95 (s, 1H), (s,1H), 8.82 (s, 1H)

4-(6-Fluoroindan-1-ylmethyl)-1H-imidazole. M.p. of hydrochloride215-222° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.76-1.88 (m, 1H), 2.23-2.35 (m, 1H),2.76-2.92 (m, 3H), 3.18 (dd, J=15.3 Hz, J=5.3 Hz, 1H), 3.46-3.56 (m,1H), 6.86-6.92 (m, 2H), 7.17-7.20 (m, 1H), 7.31 (s, 1H), 8.83 (s, 1H)

4-(5-Fluoroindan-1-ylmethy)-1H-imidazole. M.p. of hydrochloride 185-189°C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.76-1.88 (m, 1H), 2.23-2.35 (m, 1H),2.79-2.98 (m, 3H), 3.16 (dd, J=15.3 Hz, J=5.3 Hz, 1H), 3.43-3.53 (m,1H), 6.83-6.96 (m, 2H), 7.08-7.13 (m, 1H), 7.29 (s, 1H), 8.82 (s, 1H)

4-(4-Methoxyindan-1-ylmethyl)-1H-imidazole. M.p. of hydrochloride202-210° C.

¹H-NMR (as HCl-salt, MeOH-d₄): 1.73-1.82 (m, 1H), 2.18-2.30 (m, 1H),2.72-289 (m, 3H), 3.14 (dd, J=15.0 Hz, J=5.5 Hz, 1H), 3.48-3.56 (m, 1H),3.80 (s, 3H), 6.72-6.78 (m, 2H), 7.14 (t, 1H), 7.24 (s, 1H), 8.79 (s,1H)

4-(6-Methoxy-7-methylindan-1-ylmethyl)-1H-imidazole. M.p. ofhydrochloride 152-158° C.

¹NMR (as HCl-salt, MeOH-d₄): 1.86-1.93 (m, 1H), 2.11 (s, 3H), 2.12-2.20(m, 1H), 2.68-2.96 (m, 4H), 3.52-3.59 (m, 1H), 3.79 (s, 3H), 6.75 (d,J=8.2 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 8.79 (s, 1H)

EXAMPLE 13

4-[1-(Indan-1-yl)-ethyl]-1H-imidazole

The procedure of Example 12 is repeated except that1-(3-benzyl-3H-imidazol-4-yl)-ethanone is used in place of3-benzyl-3H-imidazole-4-carbaldehyde. The product contains twodiastereomers ad and bc (78% of ad and 22% of bc).

¹H NMR (as HCl-salt, MeOH-d₄): 1.23 (d, J=7.1 Hz, —CH₃, bcdiastereomer), 1.38 (d, J=7.1 Hz, —CH₃, ad diastereomer), 1.81-2.32 (m,2H), 2.70-2.87 (m, 2H), 3.29-3.39 (m, 1H), 3.47-3.57 (m, 1H), 6.98-7.30(m, 5H), 8.77 (s, 1H, ad (diastereomer), 8.84 (s, 1H, bc diastereomer)

Using the same method the following substituted derivative was prepared:

4-[1-(6-Methoxyindan-1-yl)-ethyl]-1H-imidazole

The reaction mixture contains two diastereomers ad and bc, which areseparated by flash chromatography eluting with methylenechloride-methanol solution.

¹H NMR (ad diastereomer as HCl-salt, MeOH-d₄): 1.37 (d, J=7.1 Hz, 3H),1.83-1.94 (m, 1H), 2.20-2.33 (m, 1H), 2.58-2.77 (m, 2H), 3.30-3.39 (m,1H), 3.43-3.49 (m, 1H), 3.74 (s, 3H), 6.63 (d, J=2.4 Hz, 1H), 6.73 (dd,J=8.2 Hz, J=2.4 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 7.13 (s, 1H), 8.74 (s,1H)

¹H NMR (bc diastereomer as HCl-salt, MeOH-d₄): 1.23 (d, J=7.1 Hz, 3H),1.90-2.01 (m, 1H), 2.05-2.16 (m, 1H), 2.70-81 (m, 2H), 3.29-3.39 (m,1H), 3.43-3.54 (m, 1H), 3.72 (s, 3H), 6.54 (d, J=2.4 Hz, 1H) 6.73 (dd,J=8.2 Hz, J2.4 Hz, 1H) 7.11 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 8.84 (s,1H)

EXAMPLE 14

4-(5-tert-Butyl-6-methoxyindan-1-ylmethyl)-1H-imidazole

Sulfuric acid (0.5 ml) is added into the mixture of4-(6-methoxyindan-1-ylmethyl)-1H-imidazole hydrochloride (50 mg) andtert-butanol (2 ml). The mixture is stirred at 35-40° C. for 10 hours.The reaction mixture is then poured into water and is made alkaline withsodium hydroxide. The product is extracted into methylene chloride whichis washed with water, dried with sodium sulfate and evaporated todryness. The residue consisting of crude product is converted to itshydrochloride salt in ethyl acetate. The yield is 23 mg, m.p. 174-184°C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.33 (s, 9H), 1.71-1.83 (m, 1H),2.19-2.31 (m, 1H), 2.73-2.89 (m, 3H), 3.15 (dd, J=15.0 Hz, J=5.1 Hz,1H), 3.40-3.50 (m. 1H), 3.77 (s, 3 H), 6.69 (s, 1H), 7.11 (s, 1H), 7.27(s, 1H), 8.81 (s, 1H)

Using the same method the following compound was prepared:

4-(6-tert-Butyl-5-methoxyindan-1-ylmethyl)-1H-imidazole

¹H NMR (as HCl-salt, MeOH-d₄): 1.30 (s, 9H), 1.73-1.84 (m, 1H),2.21-2.33 (m, 1H), 2.75-2.94 (m, 3H), 3.05 (dd, J=14.9 Hz, J=6.3 Hz,1H), 3.35-3.45 (m, 1H), 3.80 (s, 3H), 6.83 (s, 1H), 6.86 (s, 1H), 7.23(s, 1H), 8.81 (s, 1H)

5,7-Di-tert-butyl-1-(1H-imidazol-4-ylmethyl)-indan-4-ol

¹H NMR (as HCl-salt, MeOH-d₄): 1.39 (s, 9H), 1.41 (s, 9H), 1.87-1.93 (m,1H), 2.01-2.06 (m, 1H), 2.66-2.75 (m, 3H), 2.89-2.95 (m, 1H), 3.82-3.89(m, 1H), 7.15 (s, 1H), 7.33 (s, 1H), 8.77 (s, 1H)

6-tert-Butyl-1-(1H-imidazol-4-yl)-indan-5-ol

¹H NMR (as HCl-salt, MeOH-d₄): 1.32 (s, 9H), 2.06-2.15 (m, 1H),2.52-2.63 (m, 1H), 2.82-3.02 (m, 2H), 4.46 (t, ₁H), 6.69 (s, 1H), 6.88(s, 1H), 7.25 (s, 1H), 8.79 (s, 1H)

4-(6-tert-Butyl-4-methylindan-1-yl)-1H-imidazole. M.p. of hydrochloride235-242° C.

¹H NMR (as HCL-salt, MeOH-d₄): 1.25 (s, 9H), 2.09-2.19 (m, 1H),2.57-2.67 (m, 1H), 2.84-3.07 (m, 2H), 4.55 (t, 1H), 6.91 (s, 1H), 7.12(s, 1H), 7.25 (s, 1H), 8.74 (s, 1H)

5,7-Di-tert-Butyl-3-(1H-imidazol-4-yl)-indan-4-ol. M.p. of hydrochloride216-222° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.35 (s, 9H), 1.39 (s, 9H), 2.11-2.18 (m,1H), 2.44-2.52 (m, 1H), 3.06-3.16 (m, 2H), 459-4.63 (m, 1H), 6.78 (s,1H), 7.23 (s, 1H), 8.75 (s, 1H)

EXAMPLE 15

3-(1H-Imidazol-4-ylmethyl)-indan-5-ol

A stirred mixture of 4-(6-methoxyindan-1-ylmethyl)-1H-imidazolehydrochloride (140 mg) and 48% hydrobromic acid (7 ml) is heated underreflux for 45 minutes. The cooled reaction mixture is poured into waterand is made basic with ammonium hydroxide solution. The product isextracted into ethyl acetate which is washed with water, dried withsodium sulfate and evaporated to dryness. The crude product is covertedto its hydrochloride salt in ethyl acetate. M.p. 206-208° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.70-1.81 (m, 1H), 2.18-2.29 (m, 1H),2.70-2.88 (m, 3H), 3.12 (dd, J=15.3 Hz, J=5.8 Hz, 1H), 3.38-3.46 (m,1H), 6.53 (d, J=2.2 Hz, 1H), 6.60 (dd, J=8.1 Hz, J=2.2 Hz, 1H), 7.01 (d,J=8.1 Hz, 1H), 7.27 (s, 1H), 8.81 (s, 1H)

Using the same method the following compounds were prepared:

1-(1H-Imidazol-4ylmethyl)-indan-5-ol. M.p. of hydrochloride 159-161° C.

¹H NMR (as HCl-salt, MeOH-d₄); 1.69-1.80 (m, 1H), 2.17-2.29 (m, 1H),2.71-2.89 (m, 3H), 3.11 (dd, J=14.8 Hz, J=5.7 Hz, 1H), 3.35-3.45 (m,1H), 6.57 (dd, J=8.1 Hz, J=2.2 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 6.89 (d,J=8.1 Hz, 1H), 7.24 (s, 1H), 8.79 (s, 1H)

1(1H-imidazol-4-ylmethyl)-indan-5,6-diol

¹H NMR (as HCl-salt, MeOH-d₄): 1.67-1.78 (m, 1H), 2.15-2.27 (m, 1H),2.65-2.85 (m, 3H), 3.05 (dd, J=15.1 Hz, J=5.8 Hz, 1H), 3.30-3.40 (m,1H), 6.51 (s, 1H), 6.63 (s, 1H), 7.24 (s, 1H), 8.80 (s, 1H)

6-tert-Butyl-3-(1H-imidazol-4-ylmethyl)-indan-5-ol

¹H NMR (as HCl-salt, MeOH-d₄): 1.35 (s, 9H), 1.69-1.79 (m, 1H),2.18-2.28 (m, 1H), 2.69-2.86 (m, 3H), 3.08 (dd, J=15.0 Hz, J=6.0 Hz,1H), 3.35-3.43 (m, 1H), 6.46 (s, 1H), 7.04 (s, 1H), 7.26 (s, 1H), 8.81(s, 1H)

6-tert-Butyl-1-(1H-imidazol)-4-ylmethyl)-indan-5-ol. M.p. ofhydrochloride 229-230° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.32 (s, 9H), 1.72-1.81 (m, 1H),2.18-2.29 (m, 1H), 2.72-2.87 (m, 3H), 3.03 (dd, J=15.1 Hz, J=6.5 Hz,1H), 3.32-3.40 (m, 1H), 6.59 (s, 1H), 6.79 (s, 1H), 7.23 (s, 1H), 8.81(s, 1H)

3-(1H-Imidazol-4-ylmethyl)-6,7-dimethylindan-5-ol. M.p. of hydrochloride229-238° C.

H NMR (as HCl-salt, MeOH-d₄): 1.66-1.78 (m, 1H), 2.08 (s, 3H), 2.13 (s,3H), 2.14-2.26 (m, 1H), 2.66-2.85 (m, 3H), 3.06 (dd, J=15.1 Hz, J=5.8Hz, 1H), 3.35-3.43 (m, 1H), 6.39 (s, 1H), 7.22 (s, 1H), 8.79 (s, 1H)

3-(1H-imidazol-4-ylmethyl)-4,7-dimethylindan-5-ol

¹H NMR (as HCl-salt, MeOH-d₄): 1.85-1.93 (m, 1H), 2.07 (s, 3H), 2.11 (s,3H), 2.11-2.20 (m, 1H), 2.65-2.77 (m, 3H), 2.90 (dd, J=15.1 Hz, J=4.6Hz, 1H), 3.49-3.57 (m, 1H), 6.47 (s, 1H), 7.19 (s, 1H), 8.79 (s, 1H)

3-[1-(1H-Imidazol-4-yl)-ethyl]-indan-5-ol (mixture of two diastereomersad and bc)

¹H NMR (base, CDCl₃+MeOH-d₄): 1.12 (d, J=7.0 Hz, —CH₃, ad diastereomer),1.22 (d, J=7.1 Hz, —CH₃, bc diastereomer)

3-(1H-Imidazol-4-ylmethyl)-6-methylindan-5-ol

¹H NMR (as HCl-salt, MeOH-d₄): 1.68-1.79 (m, 1H), 2.13 (s, 3H),2.15-2.27 (m, 1H), 2.68-2.86 (m, 3H), 3.08 (dd, J=15.3 Hz, J=5.8 Hz,1H), 3.36-3.43 (m, 1H), 6.49 (s, 1H), 6.90 (s, 1H), 7.25 (s, 1H), 8.81(s, 1H)

1-(1H-imidazol-4-ylmethyl)-indan4-ol. M.p. 199-205° C.

¹H NMR (MeOH-d₄): 1.68-1.80 (m, 1H), 2.10-2.22 (m, 1H), 2.60-2.86 (m,3H), 3.00 (dd, J=14.6 Hz, J=5.3 Hz, 1H), 3.38-3.48 (m, 1H), 6.56 (d,J=7.8 Hz, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.71 (s, 1H), 6.94 (t, J=7.8 Hz,1H), 7.56 (s, 1H)

EXAMPLE 16

4-(1,2,3,4-Tetrahydronaphthalen-1-ylmethyl)-1H-imidazole

The procedure of Example 12 is repeated except that 1-tetralone is usedin place of 1-indanone. The melting point of the hydrochloride salt is185-188° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.59-1.93 (m, 4H), 2.70-2.80 (m, 2H),2.96 (dd, J=14.8 Hz, J=9.5 Hz, 1H), 3.08-3.22 (m, 2H), 7.08-7.14 (m,4H), 7.25 (s, 1H), 8.81 (s, 1H)

Using the same method the following compounds were prepared:

4-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole. M.p.of hydrochloride 210-218° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.58-1.64 (m, 1H), 1.71-1.86 (m, 3H),2.50-2.60 (m, 1H), 2.66-2.74 (m, 1H), 2.96 (dd, J=14.8 Hz, J=9.5 Hz,1H), 3.05-3.18 (m, 2H), 3.79 (s, 3H), 6.73-6.77 (m, 2H), 7.09 (t, 1H),7.25 (s, 1H), 8.81 (s, 1H)

4-(6-Methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole M.p.of hydrochloride 184-191° C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.58-1.88 (m, 4H), 2.70-2.76 (m,2H), 2.93(dd, J=14.5 Hz, J=9.2 Hz, 1H), 3.04-3.32 (m, 2H), 3.74 (s, 3H), 6.63 (d,J=2.5 Hz, 1H), 6.69 (dd, 8.4 Hz, J=2.5 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H),7.24 (s, 1H), 8.81 (s, 1H)

4-(7-Methoxy-1,2,3,4-tetrahydronaphthlalen-1-ylmethyl)-1H-imidazole.M.p. of hydrochloride 180-183° C.

¹H NMR (as base, CDCl₃) 1.59-1.82 (m, 4H), 2.64-2.68 (m, 2H), 2.85 (dd,J=14.6 Hz, J=9.3 Hz, 1H), 3.01 (dd, J=14.6 Hz, J=4.8 Hz, 1H), 3.12-3.17(m, 1H), 3.72 (s, 3H), 6.68-6.71 (m, 2H), 6.78 (s, 1H), 6.97-7.00 (m,1H), 7.56 (s, 1H)

4-(4-Methyl-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole Theproduct is the mixture of two isomers ad and bc (85% ad and 15% bc).

¹H NMR (as HCl-salt, MeOH-d₄): 1.25 (d, J=7.0 Hz, —CH₃, bc isomer), 1.30(d, J=7.0 Hz, —CH₃, ad isomer), 1.50-2.10 (m, 4H), 2.80-3.04 (m, 2H),3.10-3.20 (m, 2H), 7.10-7.26 (m, 5H), 8.83 (s, 1H)

EXAMPLE 17

4-(7-tert-Butyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole

Sulfuric acid (0.75 ml) is added into the mixture of4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazolehydrochloride (75 mg) and tert-butanol (3 ml). The mixture is stirred at35-40° C. for 15 hours. The reaction mixture is poured into water and ismade alkaline with sodium hydroxide. The product is extracted intomethylene chloride which is washed with water, dried with sodium sulfateand evaporated to dryness. The residue consisting of crude product iscoverted to its hydrochloride salt in ethyl acetate. The yield is 40 mg.

¹H NMR (as HCl-salt, MeOH-d₄): 1.28 (s, 9H), 1.65-1.95 (m, 4H),2.70-2.80 (m, 2H), 2.87-3.10 (m, 3H), 3.78 (s, 3H), 6.63 (s, 1H), 6.79(s, 1H), 7.22 (s, 1H); 8.81 (s, 1H)

EXAMPLE 18

5-(1H-Imidazol-4-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-ol

A stirred mixture of4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole (220mg) and 48% hydrobromic acid (11 ml) is heated under reflux for onehour. The cooled reaction mixture is poured into water and is made basicwith ammonium hydroxide solution. The product is extracted into ethylacetate which is washed with water, dried with sodium sulfate andevaporated to dryness. The crude product is converted to itshydrochloride salt in ethyl acetate. The yield is 130 mg, m.p. 200-205°C.

¹H NMR (as HCl-salt, MeOH-d₄): 1.54-1.90 (m, 4H), 2.62-2.72 (m, 2H),2.88-3.11 (m, 3H), 6.51 (d, J=2.5 Hz, 1), 6.56 (dd, J=8.3 Hz, J=2.5 Hz,1H), 6.94 (d, J=8.3 Hz, 1H), 7.23 (s, 1H), 8.81 (s, 1H)

Using the same method the following compound was prepared:

8-(1H-Imidazol-4-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-ol. M.p. ofhydrochloride 245-251° C.

¹H NMR (as HCl-salt. MeOH-d₄): 1.53-1.89 (m, 4H), 2.60-2.70 (m, 2H),2.90-2.99 (m, 1H), 3.05-3.12 (m, 2H), 6.55-6.60 (m, 2H), 6.90 (d, J=8.0Hz, 1H), 7.24 (s, 1H), 8.80 (s, 1H)

What is claimed is:
 1. An imidazole derivative compound of formula I

wherein n is 0; R₁ is hydrogen or C₁-C₄-alkyl; R₂ is hydrogen or R₂ andR₃ together form a double bond; R₃ is hydrogen or C₁-C₄-alkyl or R₂ andR₃ together form a double bond; R₄ is hydrogen, C₁-C₄-alkyl, hydroxy orC₁-C₄-alkoxy; R₅ is hydrogen or C₁-C₄-alkyl or R₄ and R₅ together withthe carbon atom to which they are attached form a carbonyl group; R₆, R₇and R₈ are each the same or different and are independently hydrogen,C₁-C₄-alkyl or C₂-C₄-alkenyl, C₃-C₇-cycloalkyl, hydroxy, C₁-C₄-alkoxy,C₁-C₄-hydroxyalkyl, thiol, C₁-4-alkylthio, C₁₋₄-alkylthiol, halogen,trifluoromethyl, nitro, unsubstituted amino, or amino substituted withC₁-C₄-alkyl; X is —CHR₉—(CHR₁₀)_(m)—; m is 0 or 1; and R₉ and R₁₀ areeach the same or different and are independently hydrogen orC₁-C₄-alkyl; or a pharmaceutically acceptable ester or salt thereof,with the proviso that R₆, R₇, and R₈ are not hydrogen, C₁-C₄-alkyl,hydroxy, C₁-C₄-alkoxy, and/or halogen when R₃, R₄ and R₅ are allhydrogen.
 2. A compound according to claim 1, wherein m=0.
 3. A compoundaccording to claim 1, wherein R₆, R₇ and R₈ are each hydrogen.
 4. Acompound according to claim 2, wherein R₆, R₇ and R₈ are each hydrogen.5. A compound according to claim 1, wherein R₆ is C₁-C₄-alkyl atposition 4 or 6 of the indane ring and R₇ and R₈ are hydrogen.
 6. Acompound according to claim 2, wherein R₆ is C₁-C₄-alkyl at position 4or 6 of the indane ring and R₇ and R₈ are hydrogen.
 7. A compoundaccording to claim 1, wherein R₆ is C₁-C₄-alkoxy at position 7 of theindane ring and R₇ and R₈ are hydrogen.
 8. A compound according to claim2, wherein R₆ is C₁-C₄-alkoxy at position 7 of the indane ring and R₇and R₈ are hydrogen.
 9. A composition comprising at least one compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 10. Amethod for the treatment of hypertension, glaucoma, chronic or acutepain, migraine, diarrhea, common cold, ischemia, addiction to one ormore chemical substances, anxiety, or of one or more neurological,musculoskeletal, psychiatric or cognition disorders, which comprisesadministering to a subject in need of such treatment an effective amountof at least one compound according to claim
 1. 11. A method according toclaim 10, wherein the treatment is for chronic or acute pain.
 12. Amethod for the treatment of preoperative anxiety, which comprisesadministering to a subject in need of such treatment an effective amountof at least one compound according to claim
 1. 13. A method forpotentiating anesthesia, which comprises administering to a subject inneed of such potentiated anesthesia an effective amount of at least onecompound according to claim
 1. 14. A method for activatingalpha2-receptors, which comprises administering to a subject in need ofsuch activation an effective amount of at least one compound accordingto claim
 1. 15. A method for the treatment of hypertension, glaucoma,chronic or acute pain, migraine, diarrhea, common cold, ischemia,addiction to one or more chemical substances, anxiety, or of one or moreneurological, musculoskeletal, psychiatric or cognition disorders,wherein the method comprises binding alpha2-receptors with analpha2-receptor agonist, wherein the agonist comprises a compoundaccording to claim
 1. 16. A method for the treatment of preoperativeanxiety, which comprises binding alpha2-receptors with analpha2-receptor agonist, wherein the agonist comprises a compoundaccording to claim
 1. 17. An imidazole compound, which is4-(indan-1-yl)-1H-imidazole, 4-(4-methylindan-1-yl)-1H-imidazole,4-(6-methylindan-1-yl)-1H-imidazole, or4-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazole.
 18. Amethod for the treatment of glaucoma, chronic or acute pain, migraine,diarrhea, common cold, addiction to a chemical substance, anxiety, or ofone or more neurological, musculoskeletal, psychiatric or cognitiondisorders, which comprises administering to a subject in need to suchtreatment an effective amount of at least one imidazole compound offormula I

wherein n is 0; R₁ is hydrogen or C₁-C₄-alkyl; R₂ is hydrogen or R₂ andR₃ together form a double bond; R₃ is hydrogen or C₁-C₄-alkyl or R₂ andR₃ together form a double bond; R₄ is hydrogen, C₁-C₄-alkyl, hydroxy orC₁-C₄-alkoxy; R₅ is hydrogen or C₁-C₄-alkyl or R₄ and R₅ together withthe carbon atom to which they are attached form a carbonyl group; R₆, R₇and R₈ are each the same or different and are independently hydrogen,C₁-C₄-alkyl or C₂-C₄-alkenyl, C₃-C₇-cycloalkyl, hydroxy, C₁-C₄-alkoxy,C₁-C₄-hydroxyalkyl, thiol, C₁₋₄alkylthio, C₁₋₄-alkylthiol, halogen,trifluoromethyl, nitro, unsubstituted amino, or amino substituted withC₁-C₄-alkyl; X is —CHR₉—(CHR₁₀)_(m)—; m is 0 or 1; and R₉ and R₁₀ areeach the same or different and are independently hydrogen orC₁-C₄-alkyl; or a pharmaceutically acceptable ester or salt thereof.